Association of Glomerular Filtration Rate Decline With Clinical Outcomes in a Population With Type 2 Diabetes

Background: While historical rate of decline in kidney function is informally used by clinicians to estimate risk of future adverse clinical outcomes especially kidney failure, in people with type 2 diabetes the epidemiology and independent association of historical eGFR slope on risk is not well described. Objective: Determine the association of eGFR slope and risk of clinically important outcomes. Design Setting and Patients: Observational population-based cohort with type 2 diabetes in Alberta. Measurement and Methods: An Alberta population-based cohort with type 2 diabetes was assembled, characterized, and observed over 1 year (2018) for clinical outcomes of ESKD, first myocardial infarction, first stroke, heart failure, and disease-specific and all-cause hospitalization and mortality. Kidney function was defined using KDIGO criteria using the most recent eGFR and albuminuria measured in the preceding 18 months; annual eGFR slope utilized measurements in the 3 years prior and was parameterized using three methods (percentiles, and linear term with and without missingness indicator). Demographics, laboratory results, medications, and comorbid conditions using validated definitions were described. In addition to descriptive analysis, odds ratios from fully adjusted logistic models regressing outcomes on eGFR slope are reported; the marginal risk of clinical outcomes was also determined. Results: Among 336 376 participants with type 2 diabetes, the median annual eGFR slope was −0.41 mL/min/1.73 m2 (IQR −1.67, 0.62). In fully adjusted models, eGFR slope was independently associated with many adverse clinical outcomes; among those with ≤10th percentile of slope (median −4.71 mL/min/1.73 m2) the OR of kidney failure was 2.22 (95% CI 1.75, 2.82), new stroke 1.23 (1.08, 1.40), heart failure 1.42 (1.27, 1.59), MI 0.98 (0.77, 1.23) all-cause hospitalization 1.31 (1.26, 1.36) and all-cause mortality 1.56 (1.44, 1.68). For every −1 mL/min/1.73 m2 in eGFR slope, the OR of outcomes ranged from 1.01 (0.98, 1.05 for new MI) to 1.09 (1.08, 1.10 for all-cause mortality); findings were significant for 10 of the 13 outcomes considered. Limitations: Causality cannot be established with this study design. Conclusions: These findings support consideration of the rate of eGFR decline in risk stratification and may inform clinicians and policymakers to optimize treatment and inform health care system planning.


Introduction
The incidence and prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide and in North America, which impacts the epidemiology of chronic kidney disease (CKD); 1 approximately half of people with T2DM have concomitant CKD. 2 Persons with both T2DM and CKD have a high risk of adverse events, including kidney failure, cardiovascular events, mortality, and healthcare resource use. 3 Assessing the risk of future adverse clinical events may inform the appropriate use of preventative treatment and processes of care and guide health care resource planning.People with T2DM and CKD are commonly classified by KDIGO risk categories, incorporating GFR as well as the severity of albuminuria.However, other factors may also inform risk, including historical rate of loss of kidney function.
There is known variability in the rate of progression of kidney disease in persons with T2DM; however, the distribution of the rate of progression in a population-based cohort and the relationship to the KDIGO risk category is not well described.While the rate of decline in GFR is frequently used informally by clinicians as an indicator of future risk of kidney failure, the association between rate of progression of kidney disease and other adverse clinical outcomes including cardiovascular events, hospitalization, and mortality is not well described.
Understanding the distribution of the rate of progression of CKD among patients with T2DM, how the severity of progression at baseline associates with KDIGO risk categories, treatment patterns, kidney and cardiovascular outcomes, and healthcare resource use would be useful to clinicians and policymakers to identify opportunities to improve care and optimize outcomes in this growing patient population.[6][7]

Methods
This retrospective cohort study is reported according to the STROBE guidelines 8 and was conducted according to an a priori study protocol.The institutional review board at the University of Alberta (Pro00106318) approved this study and waived the requirement for participants to provide consent.

Data Source for the Cohort
We used the Alberta Kidney Disease Network database, which incorporates registry, physician claims, hospitalizations, ambulatory care utilization, and pharmaceutical information network (outpatient prescription dispensation) files from all adults registered with Alberta Health (AH; the provincial health ministry) and links them with data from provincial clinical laboratories and provincial kidney programs.This database has been widely used 3,9,10 because of its population-based coverage of a geographically defined area, including demographic characteristics, health services utilization, and clinical outcomes.Additional information on the database is available elsewhere, including the validation of selected data elements and the standardization and calibration of serum creatinine assays. 11All Alberta residents are eligible for insurance coverage by AH, and >99% participate in coverage.The database was used to assemble cohorts of adults (≥18 years) with T2DM who resided in Alberta, Canada, on December 31, 2017 (index).Participants were excluded if they had type 1 diabetes (ICD-9-CM 250.x1, 250.x3, or ICD-10-CA E10) prior to T2DM or if they had initiated renal replacement therapy prior to index (chronic dialysis or in receipt of a kidney transplant).All participants were followed until December 31, 2018, death or outmigration, whichever occurred sooner (Supplement Figure 1).
The rate of decline in eGFR before the index date was based on all available outpatient eGFR measurements over the previous 3 years.A 3-year period was used to assess change in eGFR (per year), allowing a contemporaneous assessment while maximizing data from measurements that may be infrequent.A minimum of three values were required.The median was 5, with an interquartile range of 4 to 8. The eGFR data was regressed on participants and time using mixed effects models.Both participant and participant time were modeled as random effects.The latter was annualized and formed the estimate for each participant's estimate of baseline eGFR slope.Glycated hemoglobin (A1c) was also included as an exposure.
Prescriptions included sodium-glucose cotransporter-2 (SGLT2) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and statins.Each participant was classified with baseline use if there was a new prescription within 120 days prior to baseline.As in our prior work, we used administrative data to identify age, biological sex, and rural residence location. 21

Clinical Outcomes
A 1-year time period after the assessment of baseline characteristics was used for outcome ascertainment, from January 1, 2018, to December 31, 2018.Outcomes included incidence of end-stage kidney disease, first myocardial infarction, first stroke, and new diagnosis of heart failure in participants without prior occurrences of these events.Endstage kidney disease was defined as the initiation of chronic dialysis, receipt of kidney transplant, or at least two measures of eGFR <15 mL/min/1.73m 2 30 days or more apart.Other outcomes were hospitalizations (all-cause, kidney, and cardiovascular-specific, defined as myocardial infarction, stroke, or heart failure) and mortality (all-cause, renal, and cardiovascular-specific).
In sensitivity analyses using Model 2s parameterization, we considered (1) participants with and without ACEi, ARB, or SGLT2i prescriptions and (2) did an analysis using only the covariates from the Kidney Failure Risk Equation 22: age, sex, baseline eGFR, and albuminuria.
Medication dispensation by KDIGO risk and rate of the annual eGFR decline (Supplement Figure 2) demonstrated utilization of SGLT2-inhibitors in <25% of all participants.ACE inhibitor, ARB, and statin use was between 55% and 76%, with numerically greater use at moderate to very-high KDIGO risk compared with low KDIGO risk.
Participants at very-high KDIGO risk and with ≤10th percentiles of eGFR loss accounted for most participants that developed ESKD (Supplement Figure 3); they also contributed a disproportionately large amount to other outcomes.A similar pattern is observed for all-cause hospitalization and all-cause mortality (Supplement Figure 4).
In fully adjusted models, greater annual eGFR decline was significantly associated with several adverse clinical outcomes in participants with T2DM, independent of the components of KDIGO risk (baseline eGFR and albuminuria) and other covariates (Figure 2; Supplement Table 1).Several outcomes were significantly associated with eGFR declines in the 11th to the 25th percentiles (range −3.34, −1.67 mL/min/1.73m 2 ) compared to >50th percentiles (ESKD: OR 1.50, 95% CI 1.15, 1.96; and first stroke: OR 1.12, 95% CI 1.002, 1.26).When we compared participants with eGFR decline in the ≤10th percentiles (range ≤−3.34 mL/min/1.73m 2 ) to >50th percentiles, most clinical  outcomes with the exception of first MI, hospitalization due to MI, and hospitalization due to stroke, were significantly associated with eGFR decline.When we modeled eGFR decline as a linear term, we found that every 1 mL/min/ 1.73 m 2 / year decline at baseline was associated with most clinical outcomes in the order of 1% to 10% regardless of whether we used an indicator for missing slope or whether we assumed a slope of 0 for missing slopes.In sensitivity analyses, we considered participants with and without ACEi/ ARB and/or SGLT2i prescriptions, and separately, we adjusted only for the covariates used in the KFRE 22 (Supplement Table 2).The results for both analyses were very similar to the primary analysis.
The marginal risk of clinical outcomes by the annual eGFR slope (Table 2) in a fully adjusted model demonstrates the risk for adverse clinical outcomes by observed eGFR decline.Many outcomes, including end-stage kidney disease, have relatively modest increases in marginal risk; outcomes with larger increases in marginal risk with greater eGFR decline include heart failure, all-cause hospitalization, and cardiovascular and all-cause mortality.

Discussion
In a population-based cohort of persons with T2DM, we determined the distribution of the annual slope of eGFR using a 3-year look back period, assessed the association of rate of decline with KDIGO risk categories, determined the association of KDIGO risk category and eGFR decline with clinically important outcomes, and assessed the independent association of eGFR decline at baseline on these outcomes with comprehensive adjustment including eGFR, albuminuria, comorbid conditions, A1c, and medication dispensation.A statistically significant association was observed between baseline rate of eGFR and clinically important adverse outcomes, including new diagnosis of heart failure, all-cause hospitalization, and cardiovascular and all-cause mortality.Our findings support the use of previous eGFR decline as measured by eGFR slope to assess risk not only of ESKD but also other clinically important adverse outcomes.
The median rate among the 61% of participants in whom the rate of the annual eGFR decline could be determined was relatively modest at −0.41 mL/min/1.73m 2 ; participants with eGFR slope in the 11th-25th and ≤10th percentile (median −2.31 and −4.71 mL/min/1.73m 2 , respectively) comprised a larger proportion of subjects within the higher KDIGO risk categories.Those with a rate of eGFR decline at the ≤10th percentile (median −4.71 mL/min/1.73m 2 ) comprised approximately 5% and 10% of the low and moderate KDIGO risk categories, respectively, but comprised over 25% of the very-high-risk category.This may, in part, be due to the severity of albuminuria as it is used to define KDIGO risk and is associated with increased risk of clinical outcomes.
risk.Rate of past eGFR decline in this patient population may be used by clinicians to inform future risk of kidney failure-this analysis supports this premise but also indicates that historical rate of eGFR decline is independently associated with new diagnosis of heart failure, hospitalization, and mortality, with 1% to 10% increase in the odds ratio for every 1 mL/min/1.73m 2 more rapid decline per year in eGFR.While CKD, defined by GFR and albuminuria, is well described as independently associated with cardiovascular outcomes, hospitalization, and mortality, rate of decline of eGFR may be yet another important characteristic of kidney disease that provides additional information on the risk of these events.
When the association of annual rate of eGFR decline is translated into marginal risk, it is notable that the absolute change in risk of adverse events varies by outcome.Compared with a rate of eGFR decline of −1 mL/min/1.73m 2 per year, in those with a decline in eGFR of −10 mL/ min/1.73m 2 per year, the greatest absolute change in risk of events is noted for all-cause hospitalization (12.8 to 18.2), and all-cause mortality (2.3 to 4.4) and is relatively modest for ESKD (0.2 to 0.4; noting 1 year follow-up), which may be too short to fully characterize risk of kidney failure.While it might be anticipated that the additional information provided by consideration of rate of eGFR decline may be in risk of ESKD, our findings suggest that greater additional >50th percentiles, 26th-50th percentiles, 11th-25th percentiles, and ≤10th percentiles.Only the participants in the >50th percentiles have slopes that increase (as well as decrease).The other three bins only show declines in eGFR.The specific ranges are given in Table 1.information is provided on risk of other outcomes; however, the absolute marginal risk for some outcomes may not be clinically significant.
Our findings are concordant with a recent study conducted in the United Kingdom among 30 222 subjects with T2DM in a UK primary health care setting.In adjusted analyses, eGFR slope of <−3 was associated with an increased risk of MACE, heart failure, and mortality. 235][6][7] This analysis confirms this association in a contemporary cohort, accounts for numerous factors, including treatment with ACEI/ARB and SLGT2i, considers additional clinically important outcomes, and further supports consideration of eGFR decline as a risk factor.
This study has several strengths, including a populationbased cohort design, availability of laboratory data to define KDIGO risk and eGFR decline, and multiple approaches to examining the association of eGFR decline and outcome.Limitations include the use of administrative data, which may be influenced by measurement error and misclassification.Although validated approaches to exposure and outcome determination were used where possible, these algorithms do not have perfect sensitivity and specificity; for example, the algorithm for determining diabetes has a sensitivity of 80%.Further, data is missing in many participants; while the missingness of eGFR values to determine the rate of decline was explored in varying models, missingness of other lab findings including albuminuria may have influenced results.Further, slope of eGFR was calculated but did not explicitly characterize or incorporate episodes of AKI or non-linearity.In addition, while 1 year of follow-up may be sufficient for cardiovascular outcomes, it may be too short to fully characterize the risk of kidney failure.Finally, while this study was conducted in a large population-based setting, it was in one province and may not be generalizable to all jurisdictions.

Conclusion
In this population-based cohort of participants with T2DM, rate of eGFR decline observed from the previous 3 years was associated with an increased risk of cardiovascular events including heart failure, hospitalization, and mortality (although causality cannot be assumed).While a greater proportion of participants at high or very-high KDIGO risk had greater eGFR rate of decline than those with less severe KDIGO risk, in fully adjusted analysis, eGFR rate of decline demonstrated a statistically significant association with adverse clinical outcomes.The clinical importance of eGFR rate of decline was greatest for outcomes of mortality, cardiovascular and all-cause hospitalization, and new diagnosis of heart failure.The absolute marginal risk may not be considered large for all of the outcomes considered.These findings support consideration of the rate of eGFR decline to inform risk stratification and may inform clinicians and Note.ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blockers; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HbA1c = glycated hemoglobin; MI = myocardial infarction; SGLT2 = sodium-glucose cotransporter-2; TIA = transient ischemic attack.Risk (%) with 95% confidence intervals are presented for Model 2 which parametrizes eGFR slopes that were negative with a linear term and an indicator for missing slope.Positive slopes were assigned a slope value of 0. The model also adjusted for baseline eGFR (≥90, 60-<90, 45-<60, 30-<45, 15-<30, <15 mL/min/1.73m 2 , and missing), albuminuria (none/mild, moderate, severe, missing), glycated hemoglobin (<7%, 7-8%, >8-9%, >9%, and missing), age, biological sex, rural status, comorbidities (atrial fibrillation, heart failure, coronary artery disease, peripheral artery disease, stroke, and retinopathy) and prescriptions filled (SGLT2 inhibitors, ACE inhibitors, or ARBs, and statins).
policymakers to optimize treatment and inform health care system planning.

Figure 3 .
Figure 3. Distribution of the annual eGFR slope.eGFR estimated glomerular filtration rate.In the top figure, there is the distribution of eGFR slope (mL/min/1.73m 2 per year).In the bottom figure, each participant's eGFR slope has been classified into 4 percentile bins:>50th percentiles, 26th-50th percentiles, 11th-25th percentiles, and ≤10th percentiles.Only the participants in the >50th percentiles have slopes that increase (as well as decrease).The other three bins only show declines in eGFR.The specific ranges are given in Table1.

Figure 4 .
Figure 4. Joint distribution of KDIGO stage and the annual eGFR slope.CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes.Each participant's eGFR slope (mL/min/1.73m 2 per year) has been classified into 4 percentile bins: >50th percentiles (lightest gray shading), 26th-50th percentiles (medium-light gray shading), 11th-25th percentiles (medium-dark gray shading), and ≤10th percentiles (darkest gray shading).The largest eGFR declines are those in the ≤10th percentiles bin.The heights of the bars depict the percentage of participants who fall into these eGFR slope percentiles bins.The widths of the bars depict the percentage of participants with four levels of KDIGO risk: low, moderate, high, and very high.

Table 1 .
Demographics and Clinical Characteristics by eGFR Slope.

Table 2 .
Marginal Risk of Clinical Outcomes by eGFR Slope.